title: A microRNA circuit mediates transforming growth factor-β1 autoregulation in renal glomerular mesangial cells.
abstract: Enhanced transforming growth factor-β1 (TGF-β1) expression in renal cells promotes fibrosis and hypertrophy during the progression of diabetic nephropathy. The TGF-β1 promoter is positively controlled by the E-box regulators, upstream stimulatory factors (USFs), in response to diabetic (high glucose) conditions; however, it is not clear whether TGF-β1 is autoregulated by itself. As changes in microRNAs (miRNAs) have been implicated in kidney disease, we tested their involvement in this process. TGF-β1 levels were found to be upregulated by microRNA-192 (miR-192) or miR-200b/c in mouse mesangial cells. Amounts of miR-200b/c were increased in glomeruli from type 1 (streptozotocin) and type 2 (db/db) diabetic mice, and in mouse mesangial cells treated with TGF-β1 in vitro. Levels of miR-200b/c were also upregulated by miR-192 in the mesangial cells, suggesting that miR-200b/c are downstream of miR-192. Activity of the TGF-β1 promoter was upregulated by TGF-β1 or miR-192, demonstrating that the miR-192-miR-200 cascade induces TGF-β1 expression. TGF-β1 increased the occupancy of activators USF1 and Tfe3, and decreased that of the repressor Zeb1 on the TGF-β1 promoter E-box binding sites. Inhibitors of miR-192 decreased the expression of miR-200b/c, Col1a2, Col4a1, and TGF-β1 in mouse mesangial cells, and in mouse kidney cortex. Thus, miRNA-regulated circuits may amplify TGF-β1 signaling, accelerating chronic fibrotic diseases such as diabetic nephropathy.
authors.affiliation: Gonda Diabetes Center, Beckman Research Institute of the City of Hope, Duarte, California, USA. mkato@coh.org
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Kato
authors.forename: Laura
authors.initials: L
authors.lastname: Arce
authors.forename: Mei
authors.initials: M
authors.lastname: Wang
authors.forename: Sumanth
authors.initials: S
authors.lastname: Putta
authors.forename: Linda
authors.initials: L
authors.lastname: Lanting
authors.forename: Rama
authors.initials: R
authors.lastname: Natarajan
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D001665:Binding Sites; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D024141:Collagen Type IV / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis; D018398:Homeodomain Proteins / Q000378:metabolism; D006706:Homeostasis; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D050527:Mesangial Cells / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D009154:Mutation; D009841:Oligonucleotides / Q000378:metabolism; D011401:Promoter Regions, Genetic; D013997:Time Factors; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D051720:Upstream Stimulatory Factors / Q000378:metabolism; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D020413:3' Untranslated Regions; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D024042:Collagen Type I; D024141:Collagen Type IV; D018398:Homeodomain Proteins; D051741:Kruppel-Like Transcription Factors; D035683:MicroRNAs; C539618:Mirn192 microRNA, mouse; C543719:Mirn200 microRNA, mouse; D009841:Oligonucleotides; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D051720:Upstream Stimulatory Factors; C497183:Usf1 protein, mouse; C519422:ZEB1 protein, mouse; D000071799:Zinc Finger E-box-Binding Homeobox 1; C068486:Tcfe3 protein, mouse